What is Human African Trypanosomiasis?

Human African Trypanosomiasis (HAT), also called African sleeping sickness, is a parasitic disease that is transmitted by infected tsetse flies. HAT can occur as a chronic or acute infection depending on the sub-species of parasite responsible for the infection. In either case, the disease progresses through two distinct stages. Stage 1 is the initial stage of infection and presents with non-specific symptoms including fever, rash, and fatigue. Untreated stage 1 HAT results in stage 2 disease where parasites invade the central nervous system causing severe neurological symptoms and eventually death. The symptoms resulting from central nervous system invasion include personality changes, mental deterioration, increased sleep, and eventually coma. The term “sleeping sickness” arose from the observation that patients with this disease become progressively sleepy until they eventually fail to wake up.

Global Burden

Human African Trypanosomiasis

HAT is primarily concentrated in Central Africa; 70% of all infections occur in a single country, Democratic Republic of Congo (DRC). There are a total of 37 countries in sub-Saharan Africa with endemic HAT and an estimated at risk population of nearly 60 million people. A small amount of transmission also occurs in the Eastern Mediterranean Region (<10% of all cases).

According to the World Health Organization (WHO), in 2009 the incidence of new HAT infections dropped below 10,000 cases for the first time in more than 50 years.1 Due to known underreporting, the actual prevalence of disease is estimated to be closer to 30,000 cases. Between 1999 and 2008, the incidence of chronic and acute disease declined by 62% and 58%, respectively. The severe debilitating effects of HAT, combined with the high mortality rate, result in an estimated 1.7 million DALYs lost per year.

The economic impact of HAT, in combination with zoonotic forms of the disease that affect livestock, has severely impaired agricultural development in Central Africa. It is estimated that Africa loses US$1.5 billion in revenues from agriculture annually due to the combined human and zoonotics forms of sleeping sickness.2

Causative Agent

blood smearHAT is caused by the protozoan parasite Trypanosoma brucei. Humans become infected when parasites are injected into the human by the bite of a tsetse fly. The injected parasites can replicate asexually in the blood and invade the lymphatic and central nervous systems. Tsetse flies pick up parasites from the blood of an infected person while taking a blood meal, thus continuing the lifecycle. Unlike the closely related American trypanosome parasite, T. cruziT. brucei does not appear to invade cells and convert to the intracellular form known as the amastigote. Although there is some evidence that this transition can occur in T. brucei, it appears to be rare and less significant for disease pathology than in its American cousin.

 
life cycleT. brucei parasites are transmitted through the bite of tsetse flies of the genus GlossinaT. brucei can also be transmitted from mother to child during pregnancy and be mechanically transmitted through blood products. However, the majority of transmission is attributed to the tsetse fly.
 
Parasite Sub-species Tsetse vector Area of Transmission Animal Reservoir
T. b. gambiense Glossina palpalis
Glossina tachinoides
Banks of shaded streams None
T. b. rhodesiense Glossina pallidipes
Glossina spp. (game biting)
Lightly covered bush Domestic and wild ungulates

Pathogenesis

Two forms of disease exist depending on the parasite sub-species: (1) Gambian or West African sleeping sickness is caused by Trypanosoma brucei gambiense, and (2) Rhodesian, Central, or East African sleeping sickness is caused by Trypanosoma brucei rhodesiense.

Gambian or West African sleeping sickness is the most common form of HAT, accounting for greater than 95% of cases. This form of disease is a chronic infection that begins asymptomatically and may present with non-specific symptoms such as fever and fatigue as parasites invade the lymphatic system (stage 1 disease). If left untreated, parasites can invade the central nervous system resulting in stage 2 disease and death. There is no animal reservoir for T. b. gambiense.

Rhodesian, Central, or East African sleeping sickness is less common, accounting for fewer than 5% of all cases. T. b. rhodesiense infection of humans results in acute infection and rapid progression to stage 2 disease. Rhodesian sleeping sickness is primarily a zoonotic infection with a large animal reservoir. It is likely that humans are only accidental hosts for this parasite.

Current Control Strategy

The current control strategy consists of two parts:

  1. Active case detection and treatment
  2. Vector control

Early detection of disease is essential for the treatment of HAT. Although treatment for stage 1 disease can be administered at the village level, treatment for stage 2 disease requires hospital administration and supportive care for toxic side effects. However, the non-specific symptoms of stage 1 disease make clinical diagnosis difficult. In areas of known transmission, WHO supports active screening and surveillance methods by providing free reagents, medicines, and support through mobile screening teams. Both serological (T. b. gambienseonly) and parasitological diagnostic methods are used to screen patients. By detecting and treating stage 1 disease, patients can avoid taking the toxic drugs used to treat stage 2 disease and the human reservoir of parasites harbored in asymptomatic patients is reduced.

Vector control is the second key component of HAT control programs. Several strategies are used including tsetse fly traps, introduction of sterile male flies into the environment, and avoidance of known tsetse fly habitats.

Existing Products

Drugs

Treatment of HAT depends on the species of parasite causing the infection and the stage of the disease as summarized below. NECT, a co-administration of nifurtimox and eflornithine, is the first new drug for HAT in over 25 years. Although NECT has not yet been approved by any country’s regulatory agency, it has been added to the WHO essential medicines list and is recommended by the WHO over more toxic melarsoprol for the treatment of stage 2 T. b. gambiense disease.

Parasite Sub-species Stage 1 drugs Stage 2 Drugs
T. b. gambiense Pentamidine (IM, minimal side effects) Nifurtimox-Eflornithine Co-Administration (NECT, IV, expensive but currently supplied by WHO)

Melarsoprol (IV, drug causes death in 5-10% of treated patients)
T. b. rhodesiense Suramin (IV, severe side effects) Melarsoprol (IV, results in death in 5-10% of treated patients)

Vaccines

There are currently no vaccines in use for HAT.

Diagnostics

Diagnosis of HAT is done primarily by microscopy. Both T. b. rhodesiense and T. b. gambiense can be seen in blood smears. A card indirect agglutination test (CATT) is also available for T. b. gambiense. To diagnose stage 2 disease, microscopy is performed on cerebral spinal fluid obtained by lumbar puncture. As the sensitivity of microscopy is not optimal for CSF, staging is usually done with white cell count in CSF to guide treatment. A white cell count of 5 or less is suggestive of stage 1; > or equal to 20 is suggestive of stage 2; in between is indeterminate. An easier method has been developed using rosette formation by binding white cells in the CSF to a CD3 pan marker for white cells.

References

  1. WHO African Trypanosomiasis Fact Sheet.
  2. WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

Drugs

Analysis

There is a great need for new treatments for HAT to replace the complicated and often toxic current drugs. The most advanced product is a combination therapy of nifurtimox-eflornithine (NECT) that, while not yet formally approved, has been recommended for use by the WHO since May 2009. Eflornithine is administered every 12 hours for 7 days in conjunction with nifurtimox given orally every 8 hours for 10 days. A single NECT kit to treat one patient weighs approximate 9 kg and costs around $360. While NECT represents a significant improvement over the often deadly arsenic-based melarsoprol, additional medications with simplified treatment regiments, improved safety, and reduced cost are needed.

The only other clinical stage product is fexinidazole, a nitroimidazole-based compound related in chemical structure to the compound benzinidazole that is currently used for the treatment of American trypanosomiasis (Chagas disease).

The majority of HAT drug discovery is currently in the pre-clinical and discovery phases. These projects are focusing on backup programs for clinical stage products (i.e., nitrimidazole backup program for fexinidazole and diamidine backup program for DB289, a product that was halted in phase III development), and identification of new chemical entities by means of high throughput screening, and characterization of novel compound scaffolds. As there are very few products in clinical development for HAT, a greater number and diversity of projects are needed to ensure success.

Interestingly, two of the products in development for HAT are related to products in use for American trypanosomiasis (Chagas disease). Nifurtimox (part of the NECT product) is in use for Chagas disease and fexinidazole is structurally related to benznidazole, which is also currently in use for Chagas disease. Drug development for HAT will undoubtedly benefit from active collaborative drug discovery projects with Chagas disease programs.

 StrengthsWeaknessesOpportunitiesRisks
NECT
Phase IIIAlready in use through WHOLong and complicated dosing regimen requiring hospitalization  Several toxic side effectsRapidly replacing the more toxic drug melarsoprolCost, storage, and shipment of kit may impede sustainability of this treatment strategy
Fexinidazole (DNA damage)
Phase IOrally available Crosses blood brain barrier (can work for stage 1 or stage 2 disease) Potentially improved safety profile  Preclinical data demonstrates cross-resistance between fexinidazole and nifurtimox high-lighting potential danger of fexinidazole as monotherapyPossible combination with other existing medicationsAs HAT infection becomes more rare, access to patients for clinical trials may be limited
SCYX-7158 (mechanism unknown)
Phase I Crosses blood-brain barrier (can work for stage 1 or stage 2 diseases) Effective against both parasite strains  Possible combination with other existing medications As HAT infection becomes more rare, access to patients for clinical trials may be limited

Vaccines

A preventative vaccine for HAT is considered unlikely and is not being pursued. As the total number of HAT cases and deaths is declining drastically, better case identification and management as well as improved treatments are priorities over exploratory vaccination projects.

Diagnostics

Analysis

Diagnostics that can detect stage 2 disease without lumbar puncture, as well as a test that can detect T. b. rhodesiense are the greatest diagnostic needs. There are numerous new diagnostics in development, primarily through the Foundation for Innovative New Diagnostics (FIND). Thus far these projects are in discovery and preclinical stages focusing on new nucleic acid detection assays, antibody/antigen detection assays, and disease staging assays using blood rather than cerebrospinal fluid. Highlighting the difficulty of that goal, a FIND collaboration attempting to find blood markers for HAT staging did not achieve promising results, and was put indefinitely on hold.  

 FIND is also working to improve the sensitivity of existing diagnostics by working on ways to concentrate blood samples to detect lower levels of parasitemia. The most promising candidate in that project is the lysing of red blood cells, which may  increase diagnostic sensitivity by up to twenty times. 

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for HAT. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for HAT are generally well developed. Patients with HAT are primarily located in extremely rural areas in countries with low infrastructure and high instability making clinical evaluation of new products extremely challenging.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome: Sequenced & annotated 

Key databases: TriTrypDB 

In vitro culture: Yes

Gene knock-outs: Yes 

Conditional gene knock-outs: Yes

Transposon mutagenesis: Possible

RNAi: Yes 

Other antisense technology:  Yes

Parasite viability assays:  Yes, but limited usefulness due to polycistronic transcription

Proteomics: Yes 

Crystal structures:  Not extensive

Whole-cell screening assays: Yes, multiple assays 

Enzymatic screening assays: Yes

Animal models: Yes  Mouse models available for both stage 1 and stage 2 disease infection 

Monitoring treatment efficacy:Yes, microscopy 

Availability of endpoints: Yes, clearance of parasitemia 

Availability of surrogate endpoints:  No 

Access to clinical trial patients/sites:  Yes, but most disease occurs in areas with minimal infrastructure and high levels of violence and instability

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Mouse 

Detection of endogenous antigen specific response in clinical samples:Not well characterized 

Natural immunity well characterized: No

Surrogate markers of protection: No 

Challenge studies possible: No

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: More needed for both strains of parasite

Access to clinical samples: Limited 

Possible sample types: Blood or CSF (stage 2)

Access to clinical trial patients/sites:Yes, but most disease occurs in areas with minimal infrastructure and high levels of violence and instability 

Treatment available if diagnosed: Yes

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.